Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.
Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.
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DOI：
10.1371/journal.pone.0146922
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Soria JM
中科院分区：
文献类型：
--
作者：
Martin-Fernandez L;Ziyatdinov A;Carrasco M;Millon JA;Martinez-Perez A;Vilalta N;Brunel H;Font M;Hamsten A;Souto JC;Soria JM
静脉血栓栓塞症（VTE）是一种常见疾病，已知的遗传风险因素只能解释一小部分遗传变异。然后，中间表型的分析，如凝血酶生成试验，可用于确定新的遗传危险因素，有助于静脉血栓栓塞。探讨凝血酶生成不同数量表型的遗传基础及其与静脉血栓栓塞风险的关系。在特发性血栓形成倾向2（GAIT-2）遗传分析项目的家族中测量滞后时间、凝血酶峰值和内源性凝血酶电位（ETP）。该样本由来自35个大家族的935名个体组成，这些大家族是通过特发性血栓形成倾向的先证者选择的。我们还进行了凝血酶生成表型的全基因组关联研究（GWAS）。结果显示，67%的VTE风险变异可归因于遗传因素。滞后时间、凝血酶峰值和ETP的遗传率分别为49%、54%和52%。更重要的是，我们还证明了凝血酶峰值或ETP与VTE风险之间存在正的遗传相关性。此外，凝血酶产生的主要遗传决定因素是F2基因。然而，观察到其他提示性信号。凝血酶生成表型强烈地由遗传决定。凝血酶峰值和ETP与静脉血栓栓塞的危险性有显著的遗传相关性。此外，F2被确定为凝血酶生成的主要决定因素。我们报告了提示性信号，可能会增加我们的知识来解释这种重要表型的变异性。需要进行验证和功能研究以确认GWAS结果。
Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results.